GABA (4-aminobutanoic acid) is the main inhibitory neurotransmitter in the mammalian nervous system. GABA activates three major classes of receptors, namely GABAA, GABAB and GABAC, which have different characteristics. GABAB receptor agonists are known as useful in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) (WO 01/42252) and as prokinetic and anti-tussive agents (EP 0506853). GABAB receptor agonists have also been disclosed as being useful in the treatment of emesis (WO 96/11680) and in the inhibition of transient lower esophageal sphincter relaxation (WO 98/11885).
The most studied GABAB receptor agonist is baclofen (4-amino-3-(chlorophenyl)butanoic acid), known inter alia in the Swiss patent No. CH 449,046. Baclofen has for several years been used as an antispastic agent. EP 0319482 discloses (3-aminopropyl)methylphosphinic acid (3-APMPiA) while EP 0356128 describes the use of this specific compound, as a potent GABAB receptor agonist, in therapy. EP 0181833 discloses substituted 3-aminopropylphosphinic acids (3-APPiA), which have been found to have very high affinities towards GABAB receptor sites. In analogy to baclofen, these compounds can be used as for instance muscle relaxants. EP 0463969 and FR 2722192 are both related to 4-aminobutanoic acid derivatives having different heterocyclic substituents at the 3-carbon of the butyl chain. WO 01/42252 and WO 01/41743 disclose novel compounds, which have affinity to one or more GABAB receptors, and the use of these active compounds in therapy. EP 0506853 discloses the use of GABAB selective agonists for treating cough in mammals. Structure-activity relationships of several phosphinic acid analogues with respect to their affinities to the GABAB receptor as well as their muscle relaxant effect are discussed in J Med Chem. (1995), 38, 3297 3312.
There is still a need for a cough therapy which does not have the disadvantages of influencing the respiratory rate, and which has an acceptable bioavailability. The object of the present invention is therefore to find a novel therapy for treating cough.